A variety of hormones, neurotraismitters and biologically active substances control, regulate, or adjust the functions of living bodies via specific receptors located in cell membranes. Many of these receptors mediate the transmission of intracellular signals by: activating guanine nucleotide-binding proteins (G proteins) to which the receptor is coupled. Such receptors are generically referred to as G protein coupled receptors (“GPCRs”). Binding of a specific signaling molecule to the GPCR can cause a conformational change in the receptor, resulting in a form that is able to bind and activate a G protein, thereby triggering a cascade of intracellular events that eventually leads to a biological response. Typically, GPCRs interact with G proteins to regulate the synthesis of intracellular second messengers such as cyclic AMP, inositol phosphates, diacylglycerol and calcium ions.
Chemokines are leukocyte attractants and contribute to immune processes that involve leukocyte migration. Leukocyte trafficking is highly coordinated, and a breakdown of the underlying control mechanisms might contribute to exaggerated innate immune activations, such as systemic inflammatory response syndromes or autoimmune diseases. Chemokine-induced signaling is mediated by GPCRs, and by definition their hallmark is leukocyte chemoattraction. In addition, chemokines induce cellular responses that are unrelated to leukocyte migration, like cell survival, virus-host interactions, tumor growth and metastasis, organogenesis, and angiogenesis.
GPCRs play a vital role in the signaling processes that control cellular metabolism, cell growth and motility, adhesion, inflammation, neuronal signaling, and blood coagulation. GPCR proteins also have a very important role as targets for a variety of signaling molecules which control, regulate, or adjust the functions of living bodies. GPCRs are involved in a wide variety of disorders, as is well-known in the art. The development of new GPCR modulators, e.g., agonists, partial agonists, inverse agonists and antagonists, may have therapeutic applications for treating GPCR-related disorders, including sepsis, arthritis, inflammation and autoimmune diseases.